In vitro, overexpression of the mdr-1 gene product, P-glycoprotein (Pgp), in tumor cells can confer high level resistance to natural product derived cytotoxics-anthracyclines, vinca alkaloids, epipodophyllotoxins and taxanes. Miller et al reported that Pgp was detectable by immuno-histochemistry in 1/49 (2%) of untreated but was detectable in 6/8 (75%) treated lymphomas, suggesting that Pgp conferred drug resistance (1). To test this hypothesis, we developed and tested a mdr-1 reversal strategy in relapsed lymphomas using EPOCH (doxorubicin/vincristine/ etoposide over 96-hours days 1-4, prednisone daily days 1-5, cyclophosphamide bolus day 5) and dexverapamil. Based on our results showing EPOCH to be effective and well tolerated, we began a phase II study of EPOCH in previously untreated patients with aggressive lymphomas. In this study, EPOCH doses are escalated within patients to the maximum tolerated dose (MTD). Endpoints are dose-intensity, efficacy, toxicity and molecular markers of drug resistance. We recently developed a "second generation" EPOCH regimen (EPOCH II) to replace stem cell transplant for potentially curable relapsed lymphomas and low-grade lymphomas. This regimen is based on experimental/clinical observations which suggest infusion schedules may improve the therapeutic index of natural product-derived cytotoxics, and that high dose alkylator therapy can overcome drug resistance in lymphoma. An important component is the study of immune modulation with IL-2 and peripheral blood stem cells (PBSC) on the generation of natural killer (NK) and lymphokine activated killer cells (LAK), immune recovery, and eradication of microscopic disease post-therapy (collaboration with Drs. Gress and Hakim). This approach is based on several lines of evidence (2-5): 1. T cells are largely eradicated by intensive chemotherapy; 2. Clinically relevant immune compromise is associated with T cell depletion; 3. T cell repopulation is accomplished through the thymus if the mature T cell population has been exposed to chemotherapy (but only after prolonged periods of time in older patients); 4. T cell repopulation pathways can be studied utilizing selected cell surface determinants and; 5. T cell repopulation can be influenced by cytokines, including IL-2 and IL-6. Additionally, in animal models, mature T cell precursors present in the PBSC can promote return of immunocompetence and possibly anti-tumor effects.